Tumor Suppressive Effects of GAS5 in Cancer Cells

Abstract

In recent years, long non-coding RNAs (lncRNAs) have been shown to play important regulatory roles in cellular processes. Growth arrests specific transcript 5 (GAS5) is a lncRNA that is highly expressed during the cell cycle arrest phase but is downregulated in actively growing cells. Growth arrests specific transcript 5 was discovered to be downregulated in several cancers, primarily solid tumors, and it is known as a tumor suppressor gene that regulates cell proliferation, invasion, migration, and apoptosis via multiple molecular mechanisms. Furthermore, GAS5 polymorphism was found to affect GAS5 expression and functionality in a cell-specific manner. This review article focuses on GAS5's tumor-suppressive effects in regulating oncogenic signaling pathways, cell cycle, apoptosis, tumor-associated genes, and treatment-resistant cells. We also discussed genetic polymorphisms of GAS5 and their association with cancer susceptibility.

Keywords: GAS5; growth-arrest specific transcript 5; lncRNA; polymorphism; tumor suppressor.

Figure 1

Diagram representation of GAS5 transcript (GenBank ID: NR_002578.3) with the sequence length of 656 nt encodes 10 snoRNAs within introns. The sponging regions of miRNAs predicted by miRcode [13] are located at exon 1 (hsa-mir-144), intron 1 (hsa-mir-21, hsa-mir-455-5p and hsa-mir-590-5p), exon 2 (hsa-mir-4735-3p and hsa-mir-217), exon 4 (hsa-mir-135a-5p), exon 5 (hsa-mir-33a-3p), intron 4 (hsa-mir-23a), exon 7 (hsa-mir-425 and hsa-mir-425-5p, exon 8 (hsa-mir-128), exon 9 (hsa-mir-490-3p), intron 11 (hsa-mir-196a and hsa-mir-222) and exon 12 (hsa-mir-129-5p, hsa-mir-31 and hsa-mir-10a-5p).

Figure 2

Diagram representation of (A) The minimum free energy (MFE) secondary structure of GAS5 predicted using RNA-fold web server (http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi) (accessed on 24 March 2022). (B) The secondary structure of GAS5 regions sponging miRNAs in GAS5 variant 1 is shown using forna (force directed graph layout) [28].

Figure 3

Schematic representation of proliferating cell with activated PI3K/AKT/mTOR pathway. The ribosomal S6 protein is phosphorylated (+p) when the PI3K/AKT/mTOR pathway is activated, resulting in translation and degradation of GAS5 by the NMD pathway. Downregulation of GAS5 causes an increase in c-Myc protein, thereby facilitating cell cycle progression via inducing activation of cyclin-CDK complexes. PTEN, a tumor suppressor protein, blocks the PI3K/AKT/mTOR signaling pathway by dephosphorylating (−p) PIP3.

Figure 4

GAS5 acts as a guide by directing transcription factors to the promoter region of the gene. (A) GAS5 guides transcriptional activator E2F1 to the promoter region of p27Kip1 and promotes transcription. (B) GAS5 enhances transcriptional repression by guiding the transcriptional repressor E2F4 to the promoter region of EZH2. Transcription start site (TSS).

Figure 5

Schematic representation of glucocorticoid receptor (GR) activation by glucocorticoid (GC). (A) The glucocorticoid-activated GR bind to the glucocorticoid responsive element (GRE) via the DNA binding domain (DBD) in downregulated GAS5 solid cancer cells to induce anti-apoptotic genes such as cIAP2, resulting in cell survival. (B) GAS5 acts as a GRE decoy in GAS5 elevated cells, repressing GR-mediated activation of anti-apoptotic genes and therefore sensitising cells to apoptosis.

Figure 6

Schematic representation of PI3K/AKT/mTOR pathway. GAS5 inhibits the repression of tumor suppressor gene expression such as PTEN, FOXO and p27KIP1 via sponging oncomirs. Pathway was constructed using PathwayMapper [83]. Receptor tyrosine kinase (RTK), Ras homolog enriched in brain (RHEB), Tuberous sclerosis complex 1 and 2 (TSC1 and TSC2).